Schwann cells are under investigation as candidates for therapies aimed at restoring myelin to demyelinated areas of the CNS, as well as supporting neural regeneration after spinal cord injury. Current knowledge of the mechanisms underlying entry and survival of Schwann cells in the CNS is rudimentary. A better understanding of the Schwann cell-CNS interaction would facilitate the design of strategies to promote entry of Schwann cells into the CNS and support their survival in cases where remyelination by oligodendrocytes does not take place. While Schwann cell transplants in the CNS are reported to produce some benefit, it would be far more advantageous to encourage the entry of endogenous Schwann cells from the periphery. Such a situation would allow the targeting of many more areas of the brain and spinal cord, while avoiding the surgical trauma of transplantation. Our preliminary results indicate that entry of peripheral Schwann cells can lead to extensive remyelination of the spinal cord and recovery of lost motor function. These results also show that, at longer survival times, the Schwann cells are removed and replaced by oligodendrocytes. The precise origin of the invading Schwann cells remains to be determined, as does their perseverance in the CNS in the absence of oligodendrocyte remyelination. We propose to study mechanisms of Schwann cell remyelination of the spinal cord using a new model of spinal demyelination in the rodent. In this model, rodents undergo a massive demyelination of the spinal cord followed by a diffuse primary remyelination by Schwann cells and complete neurological recovery, and finally a secondary remyelination by oligodendrocytes. We will determine the origin of Schwann cells entering the lateral spinal cord adjacent to adherent dorsal root. Furthermore, we will study the mechanisms by which a Schwann cell, after having myelinated a central axon, is induced to demyelinate, and leave (desheath) the axon. These mechanisms are proposed to be similar to those responsible for the de-differentiation of Schwann cells in the periphery following axonal injury and involve nerve growth factor and one of its receptors, the p75 receptor. We will also examine the fate of Schwann cells both in the presence and absence of oligodendrocyte precursor cells. While replacement by dividing oligodendrocyte precursor cells could lead to Schwann cell death, it is unknown whether the absence of oligodendrocytes capable of restoring central nervous system myelin might permit permanent Schwann cell remyelination of the CNS.